The present invention relates to new aromatic di-keto derivatives, and to their pharmaceutically acceptable salts, esters, ethers, and other chemical equivalents. The di-keto derivatives are glucose-6-phosphate translocase inhibitors, and can be used in the treatment of diabetes mellitus. The present invention further relates to a process for the production of the di-keto derivatives, to the use of the di-keto derivatives and their pharmaceutically acceptable salts, esters, ethers, and other chemical equivalents as pharmaceuticals, in particular to their use in the treatment of diabetes mellitus, and to pharmaceutical compositions comprising the di-keto derivatives, pharmaceutically acceptable salts, esters, ethers, or other chemical equivalents thereof.
Increased rate of hepatic glucose output is a general feature of diabetes mellitus. In particular, a strong correlation exists between fasting plasma glucose level in non-insulin dependent diabetes mellitus (NIDDM) and hepatic glucose output. The two pathways by which glucose is produced in the liver are gluconeogenesis and glycogenolysis. The terminal steps of both pathways are catalyzed by the microsomal glucose-6-phosphatase, a key enzyme in the homeostatic regulation of blood glucose levels. The level of this enzyme has also been known to be elevated in both experimental and pathological conditions of diabetes. Interference with this enzyme system should, therefore, result in a reduced hepatic glucose production.
Hepatic glucose-6-phosphatase is a multicomponent system comprised of at least three functional activities: a glucose-6-phosphate translocase (T1), a glucose-6-phosphate phosphohydrolase and a phosphate/pyrophosphate translocase (T2). The glucose-6-phosphate translocase facilitates transport of glucose-6-phosphate into the lumen of the endoplasmic reticulum (ER). The phosphohydrolase, with its active site situated on the lumenal surface of the ER, hydrolyzes glucose-6-phosphate and releases glucose and phosphate into the lumen. While the efflux of phosphate is facilitated by the phosphate/pyrophosphate translocase, the exact mechanism of glucose efflux is still not clear.
The high degree of substrate specificity of glucose-6-phosphate translocase makes this a potential target for pharmacological intervention in the treatment of diabetes mellitus. Thus, amongst physiologically occurring sugar phosphates, only glucose-6-phosphate is transported by the translocase. In contrast, the phosphatase is non-specific and is known to hydrolyse a variety of organic phosphate esters.
A series of non-specific inhibitors of glucose-6-phosphatase has been described in the literature, e.g. phlorrhizin (J. Biol. Chem. 242, 1955-1960 (1967)), 5,5xe2x80x2-dithio-bis-2-nitrobenzoic acid (Biochem. Biophys. Res. Commun. 48, 694-699 (1972)), 2,2xe2x80x2-diisothiocyanatostilbene and 2-isothiocyanato-2xe2x80x2-acetoxystilbene (J. Biol. Chem. 255, 1113-1119 (1980)). The first therapeutically utilizable inhibitors of the glucose-6-phosphatase system are proposed in EP-A-587 087 and EP-A-587 088. Kodaistatins A, B, C, and D described in PCT/EP 98/02247 are the first glucose-6-phosphate translocase inhibitors from microbial sources.
The aromatic di-keto derivatives according to the present invention may be derived from a compound named mumbaistatin. Mumbaistatin is described in PCT/EP99/04127. It is a natural product obtainable by cultivation of the microorganism Streptomyces litmocidini, a sample of which was deposited on Jul. 4, 1997, with the German Collection of Microorganisms and Cell Cultures (DSMZ) under accession no. DSM 11641.The structural formula of mumbaistatin has now been determined and is given below: 
It has been found that certain derivatives of mumbaistatin have improved activity and are better tolerated in the mammalian body than mumbaistatin itself. Also, the separated diastereomers of mumbaistatin have advantages over the mumbaistatin mixture of diastereomers.
The present invention accordingly provides compounds of the general formula I 
wherein:
R4, R5, R6 and R7 are independently selected from H, OH, halogen, optionally substituted alkyl, aryl or acyl, X-alkyl, and X-aryl, where X is O, NH, N-alkyl or S,
K is a group of formula II or III: 
L is a group of formula IV or V: 
or K and L form, together with the respective carbon atoms to which they are bound, a group of formula VI, VII, or VIII: 
xe2x80x83wherein:
R1 and R3 are independently selected from a cation, H, alkyl, and aryl,
R2 is H, alkyl, aryl, or acyl,
X1, X2, X3, X4, X5, X6 and X7 are independently selected from O, NH, N-alkyl and S, and the Cyclus is, together with the C-atoms marked cxe2x80x2 and dxe2x80x2 an optionally substituted saturated, partly unsaturated or aromatic, carbocyclic or heterocyclic, simple or condensed ring system, and its pharmaceutically acceptable salts, esters and ethers and other chemical equivalents in all their stereoisomeric and tautomeric forms and mixtures thereof in any ratio with the exclusion of the compound where K is a group of formula II, and L is a group of formula IV in which X1, X2, X3, X4, X5, X6 and X7 are O, R1, R2 and R3 are H, R4 is OH, R5, R6 and R7 are H, and Cyclus is 3,8, di-hydroxy anthraquinone, and the compound where K and L form together a group of formula VI in which X1, X2, X3, X4, X5, X6 and X7 are O, R1 is CH3, R2 and R3 are H, R4 is OH, R5, R6 and R7 are H, and Cyclus is 3,8-dihydroxy anthraquinone.
The present invention furthermore includes compounds of the general formula IX 
wherein:
M is a group of formula X 
N is a group of formula XI
xe2x80x94X5R3xe2x80x83xe2x80x83XI
or M and N form, together with the C atom to which they are bound, a residue of formula XII 
xe2x80x83which is bonded through the C atom marked e
O is a group of formula XIII 
xe2x80x83and
P is a group of formula XIV
xe2x80x94X5R2xe2x80x83xe2x80x83XIV
or O and P form, together with the C atom to which they are bound, a residue of formula XV 
xe2x80x83which is bonded through the C atom marked f
wherein R1 to R7, X1 to X7, Cyclus, c and d are as defined in claim 1, and its pharmaceutically acceptable salts, esters and ethers and other chemical equivalents in all their stereoisomeric and tautomeric forms and mixtures thereof in any ratio.
The term xe2x80x98alkylxe2x80x99 as used herein represents a straight or branched, optionally substituted C1-C6-alkyl, preferably a C1-C4-alkyl such as: methyl, ethyl, n-propyl, i-propyl, n-butyl, or i-butyl, a straight or branched, optionally substituted, C2-C6-alkenyl, preferably C2-C4-alkenyl such as allyl, a straight or branched, optionally substituted C2-C6-alkynyl, preferably C2-C4-alkynyl such as allylene.
The term xe2x80x98arylxe2x80x99 as used herein represents an optionally substituted benzyl or phenyl.
The term xe2x80x98acylxe2x80x99 as used herein represents an optionally substituted aliphatic, aromatic, or heterocyclic acyl, for example C1-C4aliphatic acyl, such as acetyl or propionyl, aromatic acyl, such as benzoyl or toluyl, and heterocyclic acyl which is derived from 5- or 6-membered rings with 1-4 hetero atoms, such as, nicotinoyl, furyl, pyrrolyl, thienyl, thiazolyl and oxazolyl.
xe2x80x98Optionally substitutedxe2x80x99 as used herein means that the group in question is optionally substituted by one or more, preferably 1, 2, 3, or 4, identical or different substituents selected from: hydroxyl, C1-C4alkyl, C1-C4alkenyl, C1-C4alkoxy, C1-C4alkylthio, C1-C4alkoxycarbonyl, carbamoyl, carboxyl, trifluoromethyl, cyano, nitro, amino, C1-C4alkylamino, diC1-C4alkylamino, amidino, aryloxy, arylamino and halogen.
Halogen represents I, Br, Cl, or F, preferably Cl or Br.
The term xe2x80x98cationxe2x80x99 represents an inorganic metal ion or an organic ammonium ion. Examples are pharmacologically acceptable alkali metal ions or alkaline earth metal ions, preferably sodium, potassium, calcium, or magnesium ion, the ammonium ion and, from the organic ammonium ions, in particular, an optionally substituted alkylated ammonium ion, such as, for example, the triethylammonium or diethanolammonium ion, as well as the morpholine, benzylammonium and procaine, L-arginine and L-lysine ions.
The Cyclus ring, which includes the carbon atoms marked xe2x80x98cxe2x80x99 and xe2x80x98dxe2x80x99 in the formulae, may represent an optionally substituted, saturated, partly unsaturated or aromatic, carbocyclic or heterocyclic, simple or condensed ring system. A simple ring system means a monocyclic ring containing 3 to 6 ring atoms and a condensed ring system means a condensed dicyclic or tricyclic ring containing 6 to 14 ring atoms.
The saturated carbocyclic ring system may represent a 3 to 14 membered ring system, preferably a simple 3 to 8 membered ring such as cyclo-C3-C8alkyl, more preferably cyclo-C3-C6alkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. It may also represent a bi- or tri-cyclic condensed ring system such as bicyclo[3.3.1]nonane or tetradecahydrophenanthrene.
The partly unsaturated carbocyclic ring system differs from the saturated carbocyclic ring system in having one or two double or triple bonds. Thus, it may represent a 3 to 14 membered ring system, preferably a 3 to 8 membered ring such as cyclo-C3-C8alkene, for example, cyclopentadiene or cyclooctatetraene, more preferably cyclo-C3-C6alkene, or cyclo-C5-C8alkyne.
The aromatic carbocyclic simple or condensed ring system may represent a 5 to 14 membered monocyclic, dicyclic or tricyclic ring system such as phenyl, naphthyl, phenanthrene, or anthraquinone.
The heterocyclic ring system may be saturated, partly unsaturated, or aromatic and may be a simple or condensed ring system as defined above. The heterocyclic ring system represents the carbocyclic ring system as defined above in which 1, 2, 3, or 4 of the C atoms are replaced by identical or different heteroatoms selected from N, O and S. It may, for example, represent a 5- or 6-membered ring which has 1 to 4 heteroatoms, independently selected from O, S and N. in particular N, optionally together with S or O as ring atoms. Some examples of heterocyclic ring systems are heteroalkyls such as pyrrolidine, piperidine, tetrahydrofuran, oxazolidine and thiazolidine, and heteroaryl residues such as pyridyl, pyrimidyl, furanyl, benzothiazoyl, benzofuranyl and indolyl.
Preferably, the Cyclus is a group of formula XVI 
wherein:
R8 is H, alkyl, aryl, or acyl;
R9 is a cation, H, alkyl, aryl, or acyl;
R10, R11, R12 and R13 are independently selected from H, alkyl, xe2x80x94X10H, xe2x80x94X10R,
R10, and R11 and/or R12 and R13 together are xe2x95x90X10,
X8, X9 and X10 are independently selected from O, NH, N-alkyl and S,
R is alkyl, aryl, or acyl,
xe2x80x98 - - - - - xe2x80x99 is an optional bond, and
the Cyclus is bound by the C-atoms marked c and d.
More preferably the Cyclus ring is a residue of formula XVIA 
wherein:
X8 and X9 are independently H or O;
R8 and R9 are independently H or alkyl;
R10 to R13 are H, or R10 and R11 together and/or R12 and R13 together are a carbonyl, and the Cyclus is bound by the C-atoms marked c and d.
The Cyclus part of the structure may be any one of a variety of different ring structures. It is advantageous, however, to have a substitution, preferably hydroxyl or alkoxyl, on the Cyclus. The Cyclus is preferably an aromatic ring structure of formula XVIB below: 
wherein;
R9 is H or C1-C4-alkyl; and
X9 is O.
Preferred compounds of the present invention have the general formula XVIII: 
wherein:
R1 to R7, X1 to X7, Cyclus and c and d are as defined above, with the exclusion of the compound where X1 to X7 are O, R1, R2 and R3 are H, R4 is OH, R5, R6 and R7 are H and Cyclus is 3,8, di-hydroxy anthraquinone, and its pharmaceutically acceptable salts, esters and ethers and other chemical equivalents, in all their stereoisomeric and tautomeric forms and mixtures thereof in any ratio.
Preferably the carbon marked with an asterisk has an S configuration, in which case the exclusion mentioned above is not applicable.
Suitably, R1, R2 and R3 are C1-C6-alkyl, preferably C1-C4 alkyl, such as methyl.
Conveniently, any one or more of X1 to X7 are O.
An example of a compound of formula XVIII above is formula XVIIIA: 
A further example of a compound of formula XVIII above is formula XVIIIB: 
The alkylated mumbaisatin derivatives of formula XVIIIA and formula XVIIIB are obtained by dissolving mumbaistatin in a solvent, preferably an organic solvent such as alkanol, for example methanol, and reacting with an alkylating agent such as diazoalkane, for example diazomethane, diazoethane, or diarylmethyldiazomethane such as diphenyldiazomethane. The alkyl substituent in the above compounds of formula XVIIIA and formula XVIIIIB is preferably a C1-C4-alkyl. When the C1-C4-alkyl is methyl, for example, the methylated mumbaistatin derivatives may be obtained by reacting mumbaistain in solution with a methylating agent such as diazomethane. The mumbaistain has ideally previously been treated with acid, preferably low molecular organic acid, for example formic acid, acetic acid, or trifluoroacetic acid. The reaction product is subsequently isolated, preferably by chromatography.
Isolation of the compounds according to the present invention from the reaction medium can be effected by methods which are in themselves known and which depend on the solubility of the resulting compounds.
A further example of a compound of formula XVIII is the enantiomer of formula XVIIIC: 
wherein the C atom marked with an asterisk has the S configuration.
A further example of a compound of formula XVIII according to the present invention is formula XVIIID: 
wherein the carbon atoms marked a and b in form of a half-ketal or ketal have independently the S or R configuration.
A further example of the compound of formula XVIII is formula XVIIIE: 
Some of the preferred compounds of formula I exemplified above may be generalized as hydroxy-diketo-dicarbonic acid derivatives.
The invention further relates to compounds of the general formula XIX: 
wherein R1 to R7, X1 to X7, Cyclus and c and d are as defined above, with the exception of the compound where R1 is methyl, R4 is xe2x80x94OH, X1xe2x80x94X7 are O and the Cyclus is 3,8dihydroxyanthraquinone, and
its pharmaceutically acceptable salts, esters and ethers and other chemical equivalents in all their stereoisomeric and tautomeric forms and mixtures thereof in any ratio.
Preferably, R1 is C1-C6-alkyl, such as methyl. R4 is suitably hydroxy or C1-C6-alkoxy, such as methoxy.
An example of a compound of formula XIX is formula XIXA: 
A further example of a compound of formula XIX is formula XIXB: 
A yet further example of a compound of formula XIX is formula XIXC: 
Another example of a compound of formula XIX is the diastereomer of formula XIXD: 
wherein the C atom marked with an asterisk * has an xe2x80x98Sxe2x80x99 configuration and the C atoms marked respectively with a and b both have either an S or R configuration.
One process for the preparation of a compound of formula XIXA, XIXB, or XIXIC comprises dissolving mumbaistatin in a solvent, preferably an organic solvent, for example an alkanol such as methanol, and reacting with a methylating agent such as diazomethane. Mumbaistain has ideally previously been treated with acid such as trifluoroacetic acid. The reaction product is isolated by methods known in the art, for example, by chromatography.
Mumbaistatin is of limited stability in solution at a pH of around 6 to 9. At acid pH mumbaistatin rapidly undergoes a complex conversion, for example to the compound of formula XIXD above. Because the acid form of mumbaistain is reacted with diazomethane to produce the methylated compounds of formula XVIIIA, XVIIIB, XIXA, XIXB and XIXC above, special precautions need to be taken to ensure that native, defined methylation products are obtained It has been found that the required methylation products are obtained under cold conditions such as at temperatures of xe2x88x921xc2x0 C. to 3xc2x0 C., preferably 0xc2x0 C., and/or when the process is carried out without prolonged reaction times. It has surprisingly been possible to crystallize at least one of the methylation products by using a mixture of water and acetonitrile. This enabled determination of the structure of the compounds by X-radiation spectrometry.
Where two sets of signals were observed (ratio approx. 1.1:1.0), they corresponded to the two diastereomer forms. Both values are separated by a comma in the case where the diastereomers show different chemical shifts (the first value corresponds to the main component).
The invention also relates to a compound of the general formula XX 
wherein R1 to R7, X1 to X7, Cyclus and c and d are as defined above, and its pharmaceutically acceptable salts, esters, and ethers, and other chemical equivalents, in all their stereoisomeric and tautomeric forms and mixtures thereof in any ratio. Preferably, one or more of X1 to X7 are O.
The invention furthermore relates to compounds of the general formula XXI: 
wherein:
R1 to R7, X1 to X7, Cyclus and c and d are as defined above, and
its pharmaceutically acceptable salts, esters, and ethers, and other chemical equivalents, in all their stereoisomeric and tautomeric forms, and mixtures thereof in any ratio. Preferably, one or more of X1 to X7 are O.
The invention additionally relates to a compound of the general formula XXII 
wherein
R1 to R7, X1 to X7, Cyclus and c and d are as defined above, and
its pharmaceutically acceptable salts, esters, and ethers, and other chemical equivalents, in all their stereoisomeric and tautomeric forms, and mixtures thereof in any ratio. Preferably, one or more of X1 to X7 are O.
An example of a compound of formula XXII is given below: 
A process for the preparation of a compound of formula XXIIA comprises dissolving mumbaistatin in a solvent, preferably an organic solvent such as alkanol, and reacting with an amide source such as an ammonia solution. The process is carried out under cold conditions, preferably at a temperature of xe2x88x921xc2x0 C. to 3xc2x0 C., more preferably at 0xc2x0 C. The reaction product is subsequently isolated.
The invention furthermore relates to compounds of the general formula XXIV 
wherein:
R1 to R7, X1 to X7, Cyclus and c and d are as defined above, and
its pharmaceutically acceptable salts, esters and ethers and other chemical equivalents, in all their stereoisomeric and tautomeric forms and mixtures thereof in any ratio. Preferably, one or more of X1 to X7 are O.
The compounds according to the present invention are tautomers in which open and closed forms exist in equilibrium.
The closed structures of formula XIX to XXIV above can be converted to the open structure of formula XVIII by reaction with a suitable base. Suitable bases which can be used for the reaction are inorganic or organic bases. Thus, tertiary amines and alkali metal carbonates, such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, lithium carbonate may be used.
An example of tautomers according to the present invention in equilibrium are compounds of formula XXIIIA and XVIIIF: 
The compounds according to the invention may be converted into pharmaceutically acceptable salts and chemical equivalents, such as esters and ethers, which are all covered by the present invention. The invention also covers all salts and chemical equivalents of the present compounds which themselves are not suitable for use as pharmaceuticals but which can be used as intermediates in the preparation of pharmaceutically acceptable salts and derivatives. The invention covers the present aromatic di-keto derivatives and their salts, esters, ethers and other chemical equivalents in all their stereoisomeric forms and tautomeric forms. The salts of the derivatives (e.g. Na, K, ammonium salts) can be prepared by standard procedures known to one skilled in the art. Salts like sodium and potassium salts, for example, may be prepared by treating the present compounds with suitable sodium or potassium bases.
Esters may be prepared, for example, by reacting the present compounds with carboxylic acids in the presence of reagents such as dicyclohexylcarbodiimide (DCC), or by treating the compound with acylating agents such as acid chlorides. Other methods of preparation of esters are given in the literature, for example in J. March, Advanced Organic Synthesis, 4th Edition, John Wiley and Sons, 1992.
Ethers may be prepared, for example, from mumbaistatin by reaction with alkylating agents under basic conditions. Other methods of preparation of ethers are given in the literature, for example in Advanced Organic Synthesis, 4th Edition, J. March, John Wiley and Sons, 1992.
Other chemical equivalents include reduction or oxidation products and addition products such as hydrates. For example, the anthraquinone group of mumbaistatin may be reduced with a reducing agent to hydroquinone. The resultant product is an effective inhibitor of glucose-6-phosphate translocase with an IC50 of=xcx9c5 nM.
Glucose-6-phosphate translocase activity has been shown in several biochemical test systems for mumbaistatin. The yield of mumbaistatin from the culture filtrate of Streptomyces litmocidini is extremely low, however, which has hindered further development of the compound. Moreover, until now it has not been possible to ascertain the structural formula of mumbaistatin due of numerous factors including the compound""s inability to crystalize and its instability in solution.
A process has now been found, however, which enables the isolation of mumbaistatin from an extract in relatively high yield. The present invention accordingly provides a process for the isolation of mumbaistatin comprising extracting a culture filtrate including mumbaistatin by ion exchange chromatography at a pH of 5-8, preferably 6 or 7. Although the use of ion exchange is generally mentioned in PCT/EP99/04127, the use of ion exchange for the purpose of improving yield was not recognized. Therefore, the examples in patent application PCT/EP99/04127 did not use ion exchangers for the isolation of mumbaistatin. Additionally, in application PCT/EP99/04127, 730 liters of culture filtrate yielded merely 70 mg of pure mumbaistain. The process of the present invention allows the isolation and enrichment of mumbaistatin and mumbaistain-related compounds by means of an ion exchange process whereby yields of at least more than 50%, typically  greater than 70%, are obtained. Further, the mumbaistain obtained according to the present process has an improved IC50 of=xcx9c5 nM in comparison to the mumbaistatin obtained in PCT/EP99/04127.
In the process for the isolation of mumbaistatin according to the present invention various ion exchangers may be used. Examples are QAE-, DEAE- and THAE-anion exchangers. Particularly, substituted or unsubstituted amino groups are carried on the chosen matrix. More particularly, DEAE-anion exchangers are used, such as DEAE-SEPHAROSE FAST FLOW(copyright) or FRACTOGEL(copyright) EMD DEAE. The anion exchangers may be used in a typical manner. An organic solvent content of 5 to 85% in a buffer system may be used. It is preferable, however, that the organic solvent used has a high content of buffer system, preferably therefore, an organic solvent content of 10 to 40% in the aqueous buffer solution is used. Examples of suitable organic solvents are water-miscible organic solvents such as lower alcohols, ketones, acetonitrile, glycol, dioxane, dimethyl sulfoxide, formamide and the like. Of particular interest are solvents such as methanol, ethanol, isopropanol, and acetone.
With the process described herein,  greater than 99% pure mumbaistatin can be obtained and the compound can be enriched with a yield of more than 70%. The resultant enriched mumbaistatin may be purified in a simple manner by, for example, molecular sieve- and/or reverse-phase-chromatography.
The compounds according to the invention inhibit rat liver microsomal glucose-6-phosphate translocase. The compounds are therefore useful as pharmaceutically active ingredients, in particular in the treatment of diabetes mellitus, and more generally in the treatment or prophylaxis of conditions which are caused by, or associated with, an elevated activity of glucose-6-phosphate translocase, or of conditions in which it is intended to reduce glucose-6-phosphate translocase activity. The compounds according to the present invention and their pharmaceutically acceptable salts, esters, ethers, and other chemical equivalents can be administered to animals, particularly to mammals, and most particularly to humans, as pharmaceuticals on their own, in mixtures with one another and in the form of pharmaceutical compositions which permit enteral or parenteral administration. Accordingly, the present invention also relates to aromatic di-keto derivatives and their pharmaceutically acceptable salts, esters, ethers, and other chemical equivalents for use as pharmaceuticals and to the use of the derivatives and their pharmaceutically acceptable salts, esters, ethers and other chemical equivalents for the production of medicaments for reducing glucose-6-phosphate translocase activity, in particular for the production of medicaments for the treatment of diabetes mellitus. The present invention further relates to pharmaceutical compositions which contain an effective amount of the di-keto derivatives and/or one or more pharmaceutically acceptable salts, esters, ethers, and/or chemical equivalents thereof together with a pharmaceutically acceptable carrier.
The compounds according to the invention can be administered orally, intramuscularly, intravenously, or by other modes of administration. Pharmaceutical compositions which contain the present compounds or a pharmaceutically acceptable salt or chemical equivalent thereof, singly or in combinations, can be prepared according to standard techniques by mixing the compound(s) with one or more pharmacologically acceptable excipients and/or auxiliaries such as fillers, emulsifiers, lubricants, masking flavours, colorants, or buffer substances, and converting the mixture into a suitable pharmaceutical form such as tablets, coated tablets, capsules, or a suspension or solution suitable for enteral or parenteral administration.
Examples of auxiliaries and/or excipients are starch, tragacanth, lactose, talc, agar-agar, polyglycols, ethanol, and water. Suitable and preferred for parenteral administration are suspensions or solutions in water. It is also possible to administer the active substances directly, without vehicles or diluents, in a suitable form, for example, in capsules. Pharmaceutical compositions comprising one or more of the present compounds or a pharmaceutically acceptable salt or chemical equivalent may also contain other pharmaceutically active ingredients. As customary, the galenic formulation and the method of administration as well as the dosage range which are suitable in a specific case depend on the species to be treated and on the state of the respective condition or disease, and can be optimized using methods known in the art. On an average, the daily dose of a compound according to the present invention in a patient of about 75 mg weight is at least 0.001 mg to at most 100 mg, preferably at most 10.0 mg.
Apart from use as pharmaceutically active ingredients and as intermediates in the production of derivatives, the present compounds and their salts and chemical equivalents can also be employed as auxiliaries for diagnostic purposes, for example in in vitro diagnoses, and for research purposes in biochemical investigations in which an inhibition of glucose-6-phosphate translocase is desired.